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DC Field | Value | Language |
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dc.contributor.author | Goulart, Paula do Nascimento | - |
dc.date.accessioned | 2024-08-09T15:14:20Z | - |
dc.date.available | 2024-08-09T15:14:20Z | - |
dc.date.issued | 2021-04-29 | - |
dc.identifier.citation | GOULART, Paula do Nascimento. Acilguanidinas e guanidinas análogas de alcaloides bromopirrólicos, planejadas como inibidores seletivos de butirilcolinesterase. 2021. 214 f. Tese (Doutorado em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2021. | pt_BR |
dc.identifier.uri | https://rima.ufrrj.br/jspui/handle/20.500.14407/17705 | - |
dc.description.abstract | Os produtos naturais são uma das principais fontes de inspiração para o desenvolvimento de novos candidatos a protótipos de fármacos. Dentre os produtos de origem natural, os alcaloides bromopirrólicos são de grande interesse dos químicos medicinais por serem uma classe de metabólitos secundários exclusivamente marinhos, produzidos por esponjas, e com diversas atividades biológicas. O presente trabalho descreve o planejamento estrutural, a síntese e avaliação, in vitro e in silico, de novos derivados bromopirrólicos guanidínicos e acilguanidínicos desenhados como análogos estruturais de alcaloides marinhos oroidínicos. O planejamento estrutural se baseou em estratégias como o bioisosterismo, hibridação molecular e homologação para o planejamento de modificações nas subunidades características destes alcaloides, como a cadeia alquílica espaçadora e a subunidade guanidínica cíclica. A estratégia sintética explorou a reação de condensação entre o intermediário-chave 1-(terc-butiloxicarbonil)-3-(4,5- dibromopirrol-2-carbonil)-2-metil-2-isotioureia com diferentes aminas e posterior remoção do grupo de proteção (N-Boc) em meio ácido para a obtenção das acilguanidinas alvo. Os análogos guanidínicos acíclicos foram obtidos através da reação entre o intermediário 2-tricloroacetil-4,5- dibromopirrol, ou 2-tricloroacetil-pirrol, e amino-alquilguanidinas N,N’-bis-protegidas previamente sintetizadas, e posterior reação de desproteção em meio ácido. Foram sintetizados em bons rendimentos 32 compostos originais (68a-c; 69a-c; 50a-f; 62a-h; 62g’; 62h’; 51a-h; 51g’; 51h’), entre guanidinas e acilguanidinas (protegidas e desprotegidas), análogos sintéticos dos alcaloides marinhos oroidínicos, todos caracterizados por RMN de 1H e RMN de 13C. A triagem in vitro sobre as enzimas acetilcolinesterase (AChE) e butirilcolinesterase (BuChE) identificou a guanidina 68c como um inibidor não seletivo de AChE (CI50 de 22,8μM) e BuChE (CI50 de 27,3 μM) e 50c como um inibidor seletivo de BuChE (CI50 de 13,3μM). As acilguanidinas se destacaram como inibidores seletivos de BuChE, principalmente as acilguanidinas livres 51a e 51g com CI50 de 4,8 μM e 3,8 μM, respectivamente, e 52c, 52d e 52f com inibição da BuChE maior que 83% a 30 μM. A relação estrutura-atividade mostrou a importância da função acilguanidina livre para a inibição seletiva de BuChE, assim como a presença dos substituintes bromos no anel. Os estudos de docking molecular corroboraram os resultados experimentais mostrando a importância das subunidades bromopirrol, acilguanidina e anel benzílico para interação com os resíduos de aminoácidos presentes no sítio ativo da BuChE. Adicionalmente, a avaliação in silico das propriedades ADME e druglike mostrou que as novas guanidinas e acilguanidinas bromopirrólicas tem potencial para boa absorção gastrointestinal e bom perfil drug-likeness. | pt_BR |
dc.description.sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES | pt_BR |
dc.language | por | pt_BR |
dc.publisher | Universidade Federal Rural do Rio de Janeiro | pt_BR |
dc.subject | acilguanidinas | pt_BR |
dc.subject | guanidinas | pt_BR |
dc.subject | alcaloides marinhos | pt_BR |
dc.subject | química medicinal | pt_BR |
dc.subject | Butirilcolinesterase | pt_BR |
dc.subject | acylguanidines | pt_BR |
dc.subject | guanidines | pt_BR |
dc.subject | marine alkaloids | pt_BR |
dc.subject | medicinal chemistry | pt_BR |
dc.title | Acilguanidinas e guanidinas análogas de alcaloides bromopirrólicos, planejadas como inibidores seletivos de butirilcolinesterase | pt_BR |
dc.type | Tese | pt_BR |
dc.description.abstractOther | Natural products are one of the main sources of inspiration for development of new drug prototypes candidates. Among products of natural origin, bromopyrrolic alkaloids are of great interest to medicinal chemists because they are a class of exclusively marine secondary metabolites, produced by sponges, and with diverse biological activities. The present work describes design, synthesis and evaluation, in vitro and in silico, of new guanidines and acylguanidines bromopyrrole derivatives designed as structural analogues of oroidine marine alkaloids. Structural planning was based on strategies such as bioisosterism, molecular hybridization and homologation for planning changes in the characteristic subunits of these alkaloids, such as the spacer alkyl chain and the cyclic guanidine subunit. Synthetic strategy explored the condensation reaction between the key intermediate 1-(tert-butyloxycarbonyl)-3-(4,5-dibromopyrrol-2-carbonyl)-2-methyl-2- isothiourea with different amines and subsequent removal of the protection group (N- Boc) in acid medium to obtain the target acylguanidines. The acyclic guanidinic analogs were obtained by the reaction between the intermediate 2-trichloroacetyl-4,5- dibromopyrrole, or 2-trichloroacetyl-pyrrole, and previously synthesized N,N'-bis- protected amino-alkylguanidines, and subsequent deprotection reaction in acidic medium. We synthesized 32 original compounds (68a-c; 69a-c; 50a-f; 62a-h; 62g'; 62h'; 51a-h; 51g'; 51h') in good yields, among guanidines and acylguanidines (protected and unprotected), which are synthetic analogs of oroidinic marine alkaloids, all characterized by 1H NMR and 13C NMR. In vitro screening for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, identified guanidine 68c as a non-selective inhibitor of AChE (CI50 of 22.8μM) and BuChE (CI50 of 27.3 μM) and 50c as a selective inhibitor of BuChE (IC50 of 13.3 μM). Acylguanidines stood out as selective BuChE inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 μM and 3.8 μM, respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 μM. Structure-activity relationship showed the importance of free acylguanidine function for selective inhibition of BuChE, as well as the presence of bromine substituents in pyrrole ring. The molecular docking studies corroborated by showing the importance of bromopyrrole, acylguanidine and benzyl ring subunits for interaction with the amino acid residues in BuChE active site. Additionally, in silico evaluation of ADME and druglike properties showed that new bromopyrrole guanidines and acylguanidines have the potential for good gastrointestinal absorption and good drug-likeness properties. | en |
dc.contributor.advisor1 | Lacerda, Renata Barbosa | - |
dc.contributor.advisor1ID | https://orcid.org/0000-0002-6185-3408 | pt_BR |
dc.contributor.advisor1Lattes | http://lattes.cnpq.br/2068820144272983 | pt_BR |
dc.contributor.advisor-co1 | Kümmerle, Arthur Eugen | - |
dc.contributor.advisor-co1Lattes | http://lattes.cnpq.br/5598000938584486 | pt_BR |
dc.contributor.referee1 | Lacerda, Renata Barbosa | - |
dc.contributor.referee1ID | https://orcid.org/0000-0002-6185-3408 | pt_BR |
dc.contributor.referee1Lattes | http://lattes.cnpq.br/2068820144272983 | pt_BR |
dc.contributor.referee2 | Alves, Marina Amaral | - |
dc.contributor.referee2ID | https://orcid.org/0000-0002-8188-5554 | pt_BR |
dc.contributor.referee2Lattes | http://lattes.cnpq.br/0945374845574106 | pt_BR |
dc.contributor.referee3 | Romeiro, Nelilma Correia | - |
dc.contributor.referee3Lattes | http://lattes.cnpq.br/5103876509322346 | pt_BR |
dc.contributor.referee4 | Tinoco, Luzineide Wanderley | - |
dc.contributor.referee4ID | https://orcid.org/0000-0002-1299-6242 | pt_BR |
dc.contributor.referee4Lattes | http://lattes.cnpq.br/1183078302328411 | pt_BR |
dc.contributor.referee5 | Salles, Cristiane Martins Cardoso de | - |
dc.contributor.referee5Lattes | http://lattes.cnpq.br/3610279707231709 | pt_BR |
dc.creator.Lattes | http://lattes.cnpq.br/3473118225634771 | pt_BR |
dc.publisher.country | Brasil | pt_BR |
dc.publisher.department | Instituto de Química | pt_BR |
dc.publisher.initials | UFRRJ | pt_BR |
dc.publisher.program | Programa de Pós-Graduação em Química | pt_BR |
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dc.subject.cnpq | Química | pt_BR |
Appears in Collections: | Doutorado em Química |
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